Corticosteroides are steroid hormones related structurally to cholesterol. These hormones are synthesized in the adrenal cortex and include the glucocorticoids (e.g. cortisol), the mineralocorticoids (e.g aldosterone) as well as weak androgens and estrogens. The adrenal function, like that of the thyroid gland, is under the control of the hypothalamus (HPT) and the pituitary (PIT). When cortisol (the naturally-occuring glucocorticoid) levels drop below a setpoint, the hypothalamus releases CRH (corticotropin releasing hormone) which stimulates adrenocorticotropic hormone (ACTH) release from the pituitary. ACTH is a tropic hormone which stimulates                the synthesis and secretion of cortisol (it has minimal effects on aldosterone synthesis/secretion), and        the growth of the adrenal gland. When cortisol levels increase, this shuts off CRH and ACTH secretion (cf. FIG. 1).        
Cortisol is characterized by its properties related to the biosynthesis and metabolism of glucose and propeties related to non-specific as well as specific immunity. Due to their effects on the glucose metabolism, cortisol and natural or synthetic analogues thereof are usually named glucocorticoids. They bind to the glucocorticoid receptor (GR).
The glucocorticoid receptor is a member of a protein super family of closely related intracellular receptors which function as ligand-activated transcription factors. Other members of this super family are the mineralocorticoid receptor (MR) and the progesterone receptor (PR). MR and GR have shown to be highly homologous, thus natural and even synthetic steroids exhibit cross-reaction between these receptors. With respect to PR, its natural ligand progesterone also cross-reacts with MR and GR.
Cushing's syndrome is a disorder resulting from increased adrenocortical secretion of cortisol. Hyperfunction of the adrenal cortex may be ACTH-dependent or it may be independent of ACTH regulation, e.g. production of cortisol by an adrenocortical adenoma or carcinoma. The administration of supraphysiologic quantities of exogenous cortisol or related synthetic analogs suppresses adrenocortical function and mimics ACTH-independent glucocorticoid hyperfunction. ACTH-dependent hyperfunction of the adrenal cortex may be due to hypersecretion of ACTH by the pituitary, secretion of ACTH by a nonpituitary tumor such as small cell carcinoma of the lung (the ectopic ACTH syndrome), or administration of exogenous ACTH. While the term “Cushing's syndrome” has been applied to the clinical picture resulting from cortisol excess regardless of the cause, hyperfunction of the adrenal cortex resulting from pituitary ACTH excess has frequently been referred to as Cushing's disease, implying a particular physiologic abnormality. Patients with Cushing's disease may have a basophilic adenoma of the pituitary or a chromophobe adenoma. Microadenomas can usually be visualized by CT or, preferably, MRI scan, using a high-resolution technique augmented by gadolinium. Some micro-adenomas are difficult to visualize even with these modalities. In some cases, no histological abnormality is found in the pituitary despite clear evidence of ACTH overproduction.
Reference to Cushing's syndrome is herein intended to mean the clinical picture resulting from cortisol excess regardless of the cause, which may be also iatrogenic, both by the injection of ACTH or by the direct administration of cortisol or synthetic analogs such as prednisone, prednisolone, dexamethasone or others that are widely used in various types of diseases including alergic, asthmatic, inflammatory or immunologic. Cushing's syndrome includes in addition adrenal tumours secreting corticoids, ectopic ACTH production and Cushing's disease.
Clinical manifestations include rounded “moon” faces with a plethoric appearance. There is truncal obesity with prominent supraclavicular and dorsal cervical fat pads (“buffalo hump”); the distal extremities and fingers are usually quite slender. Muscle wasting and weakness are present. The skin is thin and atrophic, with poor wound healing and easy bruising. Purple striae may appear on the abdomen. Hypertension, renal calculi, osteo-porosis, glucose intolerance, reduced resistance to infection, and psychiatric disturbances are common. Cessation of linear growth is characteristic in children. Females usually have menstrual irregularities. An increased production of androgens, in addition to cortisol, may lead to hypertichosis, temporal balding, and other signs of virilism in the female.
Although development of antihormonal agents related to the estrogen and androgen receptors has been successful, the search for selective anti-corticoids is more restricted.
Known agents suppressing the synthesis of steroid hormones at various levels (i.e. inhibitors of enzymes which catalyze various stages of the synthesis of steroid hormones) are reviewed in J.Steroid Biochem., vol.5, p.501 (1974) and include the following:                a) derivatives of diphenylmethane, e.g. amphenon B (which suppresses the synthesis of steroid hormones at stages 11-beta-, 17- and 21- of hydroxylase);        b) derivatives of pyridine (SU-c series), e.g. metirapon (which suppresses synthesis at stage 11-beta of hydroxylase);        c) substituted alpha, alpha-glutaramides, e.g. aminoglutetimide (which impedes the synthesis of pregnenolone from cholesterol through suppression of 20-alpha-hydroxylase and C20, C22-liase;        d) steroid substances e.g. trilostan (3 beta-substituted steroid-3 beta hydroxy-5-androsten-17-one), which suppresses 3 beta-desoxysteroidhydrogenase-5.4-isomerase (Steroids, vol.32, p.257).        e) steroids of the spironolactone family which are used as rapidly dissociating anti-Mineralocorticoids (PNAS USA 71(4) p. 1431-1435 (1974).        f) a synthetic steroid described as an anti-Mineralocorticoids, ZK91587, showing specific binding properties for the kidney (Z.Naturforsch., 45b, p.711-715 (1990)) and hippocampus type I MR (Life Science, 59, p.511-21 (1996)), but not for type II GR. It may therefore be conveniently useful as a tool in the investigation of MR function in tissues containing both receptor systems.        
Agents that specifically suppress the interaction of glucocorticoid hormones with hormone receptors are:                a) Mifepriston (11 β, 17β)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one, which acts on receptors of glucocorticoid hormones to form a complex incapable of initiating mechanisms leading to glucocorticoid effect (Annals of New-York Academy of Science, vol. 761, p.5-28 (1995)).        b) non-steroid substances (J:Steroid Biochem., vol. 31, p.481-492 (1988)) e.g. drotaverina hydrochloride (a derivative of isoquinoline-1-(3.4-dietoxibene zilidene)-6.7-dietoxy-1,2,3,4-tetrahydrizoquinoline) or acetylsalicic acid (Moskovskaya Meditsina, 1990, “Receptor mechanisms of the glucocorticoid effect” by V. P. Golikov).        
To-date, the only therapeutical application for antiglucocorticoids (e.g. Mifepristone) that has been attempted in a clinical setting is to treat inoperable cases of nonpituitary Cushing's syndrome. In the case of Mifepristone (both an anti-progesterone and an anti-glucocorticoid), high doses (up to 800 mg per day) are required.
Employing a systematic application of strategies to increase activity and decrease cross-reactivity and undesirable side effects, progress has been reported in the development of antihormonal agents with greater potency and selectivity, especially in the antiestrogen and antiandrogen fields.
In EP-903'146 the synthetic steroid, 21-hydroxy-6,19-oxidoprogesterone (21OH-6OP) of formula I, is disclosed as a selective antiglucocorticoid which does not substantially cross-react with uterus-PR or kidney-MR. Said 21-hydroxy-6,19-oxidoprogesterone antiglucocorticoid could be used in the treatment of diseases associated with an excess of glucocorticoids, where an anti-glucocorticoid virtually lacking mineralocorticoid or glucocorticoid properties as well as affinity for MR or PR is desirable.
The synthesis of 21-hydroxy-6,19-oxidoprogesterone (1) and its 21-acetate (2) was first accomplished by Deghenghi in 1966 as intermediate in a synthesis of 19-hydroxy-desoxy-corticosterone, starting from 21-hydroxypregnenolone diacetate. The procedure summarized in Scheme 1 involves the use of a “hypoiodite type” reaction with lead tetraacetate (Pb(AcO)4). Compound 1 was neither isolated nor characterized, but acetylated in situ to acetate 2. Overall yield of partially purified 2 was only 8.3%. Further to the low yield, this method of preparation is generally perceived as being difficult to reproduce notably due to the formation of the chlorohydrin. 
In a more recent synthesis of 19-hydroxydeoxycorticosterone, Kirk and Yeoh (J. Chem. Soc. Perkin Trans. I, 2945 (1983)) prepared acetate 2 as an intermediate. This procedure starting from pregnenolone acetate is depicted in Scheme 2. Although full details of the first 3 steps are not given in the experimental section of their publication, according to the literature cited the yield for these steps may be estimated as ca. 34-37% giving an overall yield of acetate 2 of ca. 12% from pregnenolone acetate. 
According to a further method, depicted in Scheme 3, the remote functionalization reaction with Pb(AcO)4 and iodine under thermal or photochemical conditions is replaced with the more reproducible and “milder” HgO/iodine system under photochemical conditions and the 21-hydroxylation step is carried out with a hypervalent iodine compound (see A. S. Veleiro, M. V. Nevado, M. C. Monteserin and G. Burton, Steroids, 60, 268-272 (1995); M. Akhtar and D. H. R. Barton, J. Am. Chem. Soc., 86, 1528-1534 (1964); R. M. Moriarty, L. S. John and P. C. Du, J. Chem. Soc. Chem. Commun., 641-642 (1981). 
The above procedure starts also from pregnenolone acetate which is first converted into 21-hydroxypregnenolone diacetate. In the best case, overall yield of 1 is ca. 26%; however this product, although apparently pure according to TLC and NMR, could not be crystallized, and thus required additional purification steps by chromatography; yield of pure crystalline 1 is about 13% (19% from 21-hydroxypregnenolone diacetate). Although the acetate 2 is an intermediate in this synthetic route, complete purification could only be achieved after deacetylation (i.e. on compound 1). Furthermore, although this procedure allows the synthesis of small amounts of 1 for the initial biological tests carried out in 1996, attempts to scale up the procedure failed. Although, the currently known methods provide 21-hydroxy-6,19-oxidoprogesterone (1), they consistently give poorer yields as well as byproducts which are difficult to eliminate.